Basically substituted oximes of 5h-dibenzo-(a,d)10,11-dihydro-cycloheptenylidene and their preparation



United States Patent Int. Cl. C07d 87/40 US. Cl. 260247.5 4 Claims ABSTRACT OF THE DISCLOSURE Basically substituted oximes of H-dibenzo-[a,d]- 10,11-dihydro-cycloheptenylidene of the formula:

wherein A is a straight or branched chain alkylene of 06 carbon atoms, R and R are each hydrogen or alkyl of 1-8 carbon atoms, which may be linked with one another or with A, such as via an N, S or O hetero atom, R and R are each hydrogen, alkyl of l-4 carbon atoms, halogen, hydroxyl, nitro or amino and n is 1 or 2 and pharmaceutically acceptable non-toxic salts possess antidepressive activity in humans, anti-cataleptic activity against pharmacogenically initiated eXtrapyramidal-motoric irritations and in vitro exhibit a strong spasmolytic effect. Processes for the preparation of these compounds are described.

This is a division of application S.N. 509,608, now Patent No. 3,441,608, issued on Apr. 29, 1969.

The present invention relates to new basically substituted oximes of SH-dibenzo [a,d]-10,1l-dihydro-cycloheptenylidene, their non-toxic pharmaceutically acceptable salts and procedure for making same, the new compounds possessing useful pharmacological and pharmacodynamic properties when administered by the usual routes for these types of compounds.

Basically substituted SH-dibenzo [a,d] 10,11 dihydrocycloheptenes have achieved importance as antidepressive agents [1. med. Chem. 7 (1964) pp. 390-392; I. med. Chem. 7, 88-94 (1964); I. med. Pharm. Chem. 4, 411416 (1961)].

Basically substituted oximes of SH-dibenzo [a,d]-10,11- dihydro-cycloheptenylidene, however, have not heretofore been disclosed or described in the literature. It has noW been found that these substituted oximes of the formula:

in which A is a branched or straight alkylene chain of 0-6 carbon atoms, R, and R are each hydrogen or an alkyl radical of l8 carbon atoms, which may be linked with one another or with A, as via a hetero atom such as N, S or 0, R and R are each hydrogen, alkyl groups of 14 carbon atoms, halogen, hydroxyl, nitro or amino,

and n is 1 or 2, have valuable and useful pharmacological properties.

In animal experiments, these compounds as such or in the form of their salts with non-toxic pharmaceutically acceptable inorganic or organic acids possess strong anticataleptic activity against pharmacogenically initiated extrapyramidal-motoric irritations.

They are also active in various animal experiments which give indications of the quality of their antidepres sive (thymoleptic) activity in human beings.

The compounds have moreover a strong spasmolytic effect in vitro.

Non-toxic pharmaceutically acceptable acids which are suitable for salt formation are, e.g. acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, salicylic acid, naphthalene-1,5-disulphonic acid, phosphoric acid, hydrochloric acid, and the like.

It has further been found that the new compounds can be produced by either reacting a SH-dibenzo [a,d]-10,11- dihydrocycloheptene of the formula:

with a hydroxylamine of the formula:

or first converting with hydroxylamine into an oxime of the formula:

and then allowing the same to react, in the form of a suitable metal salt, with a halide of the formula:

R1 Halogen-GHu-m- A-N R2 in Inthese formulae, A, R R R R and n have the meanings set forth above.

EXAMPLE 1 2.08 grams of SH-dibenzo [a,d]-10,1l-dihydro-cycloheptene-S-one and 1.5 ml. of ,B-diethylamine-ethoxyamine are dissolved in 2 ml. of methanol. Methanolic hydrochloric acid is added until a pH of 3-4 is reached and the mixture is boiled under reflux overnight. The reaction mixture is then evaporated to dryness, the residue is triturated with ether and filtered off with suction. The solid residue is dissolved in water, the solution rendered alkaline and the precipitated oil is separated and converted into the hydrochloride in ether with ethereal hydrochloric acid. The hydrochloride of 5H-dibenzo[a,d]-10,ll-dihydrocycloheptenylidene-S-fl-diethylamino ethoxy amine is finally purified by recrystallization from acetone. (M.P. 169- 171C.)

EXAMPLE 2 1.15 g. of sodium are dissolved in ml. of absolute ethanol. There are added thereto portionwise 11.2 g. of 5- oximino-SH-dibenzo (a,d)-10,ll-dihydro-cycloheptene and boiled briefly. Thereafter 6.4 g. of fi-dimethylamino-ethylchloride are introduced dropwise and boiled for 4 hours H-dibenzo(a,d)- 10,1 1-dihydro-cycloheptenylidene-S- fl-dimethylamino-B-methyl ethoxy amine of M.P. 160161 C.

5H-dibenzo(a,d)-10,1 1-dihydro-cycloheptenylidene-5- 'ydimethylamino propoxy amine of M.P. 194195 C.

5H-dibenzo(a,d)-10,1 1-dihydro-cycloheptenylidene-S- fl-piperidino ethoxy amine of M.P. 160-161 C. and

SH-dibenzo (a,d)-10, 1 1-dihydro-cycl-oheptenylidene-5- 'y-morpholino-fl-dimethyl propoxy amine of M.P. 164-167 C.

The 'y-morpholino-fi-dimethyl-propyl chloride used in the Preparation of the last named compound is prepared from a-dimethyl B-morpholino-propionaldehyde by catalytic hydrogenation and then the resulting aminoalcohol is converted into the basic chloride.

Further compounds obtained according to Example 2 are the hydrochlorides of SH-dibenzo-(a,d)-10,11-dihydro-cycloheptenylene-S-v-dimethylamino-fl-methyl propoxy amine of M.P. 181 C.;

5H-dibenzo-(a,d)-10, 1 1-dil1ydro-cycloheptenylidene-S -'ypiperidino propoxy amine of M.P. 225 to 226 C.;

5H-dibenzo-(a,d)-10,1 1-dihydro-cycloheptenylidene-5- y N-methyl-piperazino propoxy amine of M.P. 239 to 240 C.; and

5H-dibenz-o-(a,d)-10, l 1-dihydro-cycloheptenylidene-5- diethyl-amino propoxy amine of M.P. 185 C.

4 EXAMPLE 3 1.3 g. of sodium are dissolved in 150 ml. of absolute ethanol. There are added thereto 11.2 g. of S-oximino-SH- dibenzo(a,-d)-10,ll-dihydro-cycloheptene. There is then introduced a solution of 6.5 g. of methyl-amino-ethylchloride in absolute ethanol with stirring for one hour at room temperature. This is warmed overnight at C. and finally boiled for 1 /2 hours under reflux. The product is suction filtered, the filtrate evaporated and the residue treated with cyclohexane. The cyclohexane extract is mixed with ethereal hydrochloric acid and the precipitated hydrochloride of 5H-dibenzo-(a,d)-10,ll-dihydro-cycloheptenylidene 5 fl-methylamino ethoxy amine melts at 196 C. after decantating the solvent and recrystalizing from acetone.

What is claimed is:

1. 5H dibenzo[a,d]-10,11-dihydro-cycloheptenylidene S-B-piperidino ethoxy amine or the hydrochloride salt thereof.

2. 5H dibe'nzo[a,d]-10,11-dihydro-cycloheptenylidene 5-'y-morpholino-fi-dimethyl-propoxy amine or the hydro chloride salt thereof.

3. 5H dibenzo[a,-d]-10,11-dihydro-cycloheptenylidene 5-v-piperidino-propoxy amine or the hydrochloride salt thereof.

4. 5H dibenzo[a,d]-10,11-dihydrocycloheptenylidene 5-'y-N-methyl-piperazino-propoxy amine or the hydrochloride salt thereof.

References Cited UNITED STATES PATENTS 3,270,055 8/1966 Engelhard et al 26O-566 ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R.

2 5 UNKTED STATES PATENT OFFICE (IERTKFTECATE 0F CORRECTION Patent No. 3, 505,321 Dat d April 7, 1970 Inventoz-(s) Siegismund Schutz and Friedrich Hoffmeister It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading please insert --Claims priority, application Germany,

F44539 IVb/12 O, filed November 26, 1964-- SIGNED Nib SF-LRU v WWW" (SEAL) vim-1.1m 1:." 8mm, 8- M 064 ddmissioner of Pu -ms 

